Craniosynostosis is a common birth defect that affects newborns (1 in 3000 live births) with manifestations of abnormal skull shape which may result in raised intracranial pressure, blockage of cerebral blood flow and airway, impaired vision and auditory functions, mental retardation and adverse psychological effects, if not corrected surgically. Both genetic and environmental factors contribute to craniosynostosis. Recently, findings implicate involvement of transcription findings, such as MSX2 and TWIST, and growth factor receptors, such as FGFR1 and involvement of transcription factors, such as MSX2 and TWIST, and growth factor receptors, such as FGFR1 and FGFR2, in several craniosynostotic syndromes. Msx2 is a member of the msh gene family. It is known to bind DNA though its homeodomain and transactivate downstream target genes, which are yet to be defined. The notion that Msx2 gene activity is critical for the normal development and maintenance of cranial sutures is supported by the Msx2 gain-of-function phenotypes in a human autosomal dominant genetic disorder of skull supported by Msx2 gain-of-function phenotypes in a human autosomal dominant genetic disorder of skull development-Boston type craniosynostosis-in our transgenic mice in which Msx2 is over- expressed. We find that Msx2 transgenic mice exhibit premature closure of calvarial sutures as a consequence of excessive bone. The precocious closure of the sagit6tal suture correlates to an increase of osteogenic progenitors in the osteogenic front. We hypothesize that the osteogenic front and the suture re critical compartments in controlling the growth of the membraneous bones in the skull. Any perturbation to the osteogenic front and/or the suture, via either genetic or epigenetic means, can result in malformation of the skull. The major objectives of this project are to: (1) investigate the effect on calvarial bone growth and suture morphogenesis as a result of Msx1 and Msx2 null mutations; (2) study the Bono Morphogenetic Protein (BMP) signaling cascade, a regulator of Msx genes, in the normal development of calvarial sutures; and (3) identify additional regulatory components involved in the morphogenesis of sutures and the formation of the osteogenic front.